1. Field of the Invention
The invention relates to tripeptide amides which are useful as analgesics and/or opiate antagonists.
2. Description of the Prior Art
Coy et al. U.S. Pat. No. 4,127,534 describes a genus of tripeptides having the structural formula EQU H-Tyr-X-Gly-Y
wherein: X is a chiral residue of a D-amino acid selected from the group consisting of D-alanine, D-leucine, D-isoleucine, D-valine, D-phenylalanine, D-tyrosine, D-tryptophan, D-serine, D-threonine, D-methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-proline, D-asparagine, D-lysine, D-arginine and D-histidine; and Y is selected from the group consisting of hydroxy, amino, aminoloweralkyl, aminodiloweralkyl [the foregoing two terms are considered incorrect and intended to mean loweralkylamino and diloweralkylamino], or lower alkoxy; and the pharmaceutically acceptable salts thereof
which are stated to be "useful as analgesics, anti-depressants, tranquilizers, sedatives or hypnotics when administered to mammalian hosts". The genus most closely approaches the presently described and claimed invention when X is a chiral residue of D-alanine, D-phenylalanine, D-serine, D-threonine, D-methionine, D-glutamic acid, D-glutamine, D-aspartic acid, D-asparagine or D-lysine and Y is loweralkylamino or diloweralkylamino.
Smolarsky U.S. Pat. No. 4,261,883 describes a genus of tripeptide and tetrapeptide amides having the structural formula ##STR1## wherein: R is alkylene of from two to three carbon atoms, preferably polymethylene, or 2-propenylene-1,3;
R' is hydrogen or alkyl of from 1 to 6, usually 1 to 4, more usually 1 to 2 carbon atoms, i.e. methyl and ethyl; PA2 X is an electron withdrawing or an electron donating group, usually of from 1 to 20, more usually of from 1 to 12 atoms other than hydrogen, which are carbon, oxygen, nitrogen or sulfur, usually carbon, oxygen and nitrogen, which is substituted on the phenyl, and may be amino, alkylamino or dialkylamino, wherein the alkyl groups are of from one to three carbon atoms; azido, nitro, cyano, halo of atomic number 9 to 53, more usually of atomic number 9 to 35; nonoxo-carbonyl of from 1 to 18, usually 1 to 12, more usually 1 to 4 carbon atoms, including amides and esters, as well as the parent acid; acyl groups of from 1 to 4, usually 1 to 2 carbon atoms; e.g. formyl and acetyl; oxy, including hydroxy and alkoxy of from 1 to 18, usually 1 to 12, more usually 1 to 3 carbon atoms, frequently of from 1 to 2 carbon atoms; thio, including mercapto and alkylthio of the same limitations as alkoxy; alkyl of from 1 to 18, usually 1 to 12, more usually 1 to 3, frequently 1 to 2 carbon atoms; where there is more than one substituent, the substituents may be the same or different; PA2 m is zero to two, usually zero to one; and PA2 n is zero to one, usually one. PA2 Ar is phenyl or phenyl substituted by methyl, fluoro, chloro or methoxy; PA2 wherein m is an integer from 1 through 5 and Ar is phenyl or phenyl substituted by methyl, fluoro, chloro or methoxy; and PA2 wherein n is an integer from 2 through 5 and X is hydroxy, amino, methylamino, dimethylamino, dimethyloxoamino, mercapto, methylmercapto, methylsulfinyl, methylsulfonyl, carboxy, carbamoyl, methylcarbamoyl or dimethylcarbamoyl;
which are stated to "provide a wide range of physiological effects, such as mood altering effects, analgesia, muscle relaxation, and blood flow regulation". The genus most closely approaches the presently described and claimed invention when R is alkylene of from two to three carbon atoms, R' is hydrogen or alkyl of 1 to 5 carbon atoms, X is methyl, fluoro, chloro or methoxy, m is one and n is zero.
Even at closest approach the C-terminal amino acid of both the Coy et al. and Smolarsky genuses is glycyl and thus still differs significantly from that of the presently described and claimed invention.
Vavrek et al. (Abstracts of International Narcotics Research Conference, July 26-30, 1981, Kyoto, Japan, Abstract P-76) describes "Tyr-D-Ala-Phe-NH.sub.2 " as possessing "25% of the activity of Met-enkephalin" "on the stimulated guinea pig ileum". At closest approach the generic aspect of the presently described and claimed invention differs from the Vavrek et al. tripeptide amide in the amino acid moiety corresponding to Phe, wherein phenyl is separated from the .alpha.-carbon atom by from two to five methylenes instead of by one. A significant difference in biological properties results. HTyrDAlaHfeNH.sub.2 (Example 9) of the presently described and claimed invention, which differs from the Vavrek et al. tripeptide amide by only one methylene, showed a potency of 120% of Met.sup.5 -enkephalin in the guinea pig ileum test, thus almost fivefold greater than that reported for the Vavrek et al. tripeptide amide.
In three tripeptide amide species which are not within the generic aspect thereof the presently described and claimed invention differs from the Vavrek et al. tripeptide amide by having one or two substituents on the amide nitrogen atom and/or a different amino acid moiety than D-Ala.